ABSTRACT The vast majority of the vector-borne disease burden on Earth is due to mosquito-transmitted pathogens, including malaria, dengue, yellow fever and parasitic round worms. Hundreds of laboratories have been employing heroic means to suppress transmission of human pathogens by mosquitoes. Almost all of this work assumes that a bite will occur. But suppose there is no bite? If there is no bite, there is no disease transmission. We are proposing the novel approach of turning biting mosquitoes into obligate non-biters by exploiting the genetic variation for biting that exists in natural populations. The feasibility of this approach is demonstrated by our recent, ground-breaking research on mosquito Wyeomyia smithii, which is the only fully inter-fertile species comprised of some populations that bite while others are obligate non-biters. Effectively, we are observing the real-time evolutionary transformation from biting mosquitoes to non-biting mosquitoes in nature. Our recent work with W. smithii determined that about 6% of the genome exhibits parallel differential gene expression in propensity to bite between BOTH naturally evolved populations AND artificially selected lines. The goal of this proposal is to test the hypothesis that expression levels of the W. smithii genes in propensity to bite also affect biting behavior in two important species, Aedes aegypti and Culex pipiens, that transmit dengue, yellow fever, West Nile, and Zika viruses as well as parasitic round worms in human populations. If our hypothesis is supported, we will have established the foundation for our long-term goals (1) to use functional genomics to identify universal non-biting genes in all mosquito vectors of disease and (2) to develop inhibitors that effectively turn biting mosquitoes into non-biting mosquitoes. In Specific Aim 1, we will select for non-biting lines of A. aegypti and C. pipiens. We will also maintain parallel replicate biting lines as controls. In Specific Aim 2, we will quantify differential gene expression in head tissue from the selected (non-biting) and control (biting) lines. We will then test the hypothesis that the same genes and metabolic pathways associated with the evolutionary transition from a biting to an obligate non-biting life history in W. smithii determine differences between selected vs. control lines in A. aegypti and C. pipiens. The research described in this proposal will provide the foundation to confirm the universality of genes determining non-biting behavior in mosquitoes and to test pharmacological and genetic strategies that suppress biting in mosquitoes that spread disease.